Leptin and insulin regulate energy balance by conveying the abundance of peripheral energy stores to the brain. In addition, leptin and insulin also act in the hypothalamus to regulate systemic insulin sensitivity and glucose homeostasis, and this function of leptin and insulin appears to be independent of their effects on feeding and adiposity. Our long-term objective is to understand the signaling mechanisms by which leptin and insulin regulate various physiologic processes. We have previously demonstrated that leptin and insulin directly stimulate PI3K signaling in key leptin and insulin target neurons in the hypothalamus. While PI3K signaling is important for insulins metabolic effects, recent pharmacological studies indicate that the PI3K signaling pathway plays an important role in mediating leptins effect on glucose homeostasis. To date, genetic evidence is still lacking to establish the functional requirement of hypothalamic PI3K signaling in energy balance and glucose homeostasis in vivo. Moreover, neuronal subgroups important for this regulation have not been identified. In this proposal, we will test the hypothesis that PI3K in leptin responsive neurons is required for proper maintenance of energy balance and glucose homeostasis. We will determine whether chronic or acute PI3K knockdown in specific leptin responsive neurons leads to altered energy balance, increased systemic insulin resistance and impaired glucose homeostasis. We will also evaluate the function of PI3K and Jak-Stat3 signaling in Pomc and Agrp neurons, two key leptin and insulin target neurons in the hypothalamus. The proposed study will elucidate the functional necessity of PI3K in mediating energy balance and glucose homeostasis, and will identify the neuronal subgroups that are important for this process. It will advance our understanding of the signaling mechanisms by which leptin and insulin regulate energy balance and glucose homeostasis, and provide insight into the etiology of obesity and type 2 diabetes.